1  6043 143 THE COMBINED PROGNOSTIC SIGNIFICANCE OF ALKALINE PHOSPHATASE AND INTRACRANIAL ARTERIAL CALCIFICATIONS IN HEMODIALYSIS PATIENTS. INTRODUCTION: THE PREVALENCE OF INTRACRANIAL ARTERIAL CALCIFICATION (ICAC) IN MAINTENANCE HEMODIALYSIS (MHD) PATIENTS IS ABOUT 90%, AND ITS SEVERITY IS CORRELATED WITH AGE, HEMODIALYSIS VINTAGE, AND MINERAL BONE DISEASE. ELEVATED CONCENTRATIONS OF CALCIUM AND PHOSPHORUS ARE NOT SUFFICIENT FOR MEDIAL CALCIFICATION BECAUSE OF INHIBITION BY PYROPHOSPHATE. ALKALINE PHOSPHATASE (ALP) PROMOTES CALCIFICATION BY HYDROLYZING EXTRACELLULAR PYROPHOSPHATE. EPIGENETIC MECHANISMS INVOLVING ALP INHIBITION BY APABETALONE WERE INVESTIGATED AS A POTENTIAL TARGET FOR PREVENTING VASCULAR CALCIFICATIONS (VCS). THIS STUDY ASSESSED THE COMBINED IMPACT OF VCS AND ELEVATED SERUM ALP ON MORTALITY AMONG CHRONIC HD PATIENTS. METHODS: VCS REPRESENTED BY ICAC WERE MEASURED SIMULTANEOUSLY WITH MINERAL BONE DISEASE PARAMETERS INCLUDING SERUM ALP OF MHD PATIENTS WHO UNDERWENT NONCONTRAST BRAIN COMPUTED TOMOGRAPHY FROM 2015 TO 2018 IN OUR INSTITUTION. RESULTS: THIS RETROSPECTIVE STUDY INCLUDED 150 MHD PATIENTS (MEAN AGE 71.3 +/- 12.1 YEARS, 60.1% MALE). OF THE TOTAL COHORT, 12 (7.8%) HAD NO BRAIN CALCIFICATIONS AND 69 (45.1%) HAD MULTIPLE INTRACRANIAL CALCIFICATIONS. CONSIDERING THE PATIENTS WITH NORMAL ALP AND NO CALCIFICATION AS THE REFERENCE GROUP YIELDED ADJUSTED ODDS RATIOS FOR ALL-CAUSE MORTALITY OF 4.6 (95% CI: 1.7-12.7) AMONG PATIENTS WITH BRAIN CALCIFICATIONS AND NORMAL ALP (P = 0.003) AND ODDS RATIOS FOR ALL-CAUSE MORTALITY OF 6.1 (95% CI: 2.1-17.7) AMONG PATIENTS WITH BRAIN CALCIFICATIONS AND ELEVATED ALP (P= 0.001). CONCLUSION: WE FOUND AN INDEPENDENT ASSOCIATION BETWEEN ICAC AND THE RISK OF DEATH AMONG MHD PATIENTS. THE COMBINED EFFECT OF ICAC AND ELEVATED ALP WAS ASSOCIATED WITH A HIGHER ODDS RATIO FOR ALL-CAUSE MORTALITY IN MHD PATIENTS AND MAY CONTRIBUTE TO THE RISK STRATIFICATION OF THESE PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2  5536  29 ROLE OF C-MIR-21, C-MIR-126, REDOX STATUS, AND INFLAMMATORY CONDITIONS AS POTENTIAL PREDICTORS OF VASCULAR DAMAGE IN T2DM PATIENTS. THE DEVELOPMENT OF TYPE 2 DIABETES MELLITUS (T2DM) VASCULAR COMPLICATIONS (VCS) IS ASSOCIATED WITH OXIDATIVE STRESS AND CHRONIC INFLAMMATION AND CAN RESULT IN ENDOTHELIAL DYSFUNCTIONS. CIRCULATING MICRORNAS PLAY AN IMPORTANT ROLE IN EPIGENETIC REGULATION OF THE ETIOLOGY OF T2DM. WE STUDIED 30 HEALTHY VOLUNTEERS, 26 T2DM PATIENTS WITH NO COMPLICATIONS, AND 26 T2DM PATIENTS WITH VCS, TO LOOK FOR NEW BIOMARKERS INDICATING A RISK OF DEVELOPING VCS IN T2DM PATIENTS. PERIPHERAL BLOOD SAMPLES WERE USED TO DETERMINE REDOX STATE, BY MEASURING THE ENDOGENOUS ANTIOXIDANT DEFENSE SYSTEM (SUPEROXIDE DISMUTASE, SOD; CATALASE, CAT; GLUTATHIONE REDUCTASE, GRD; GLUTATHIONE PEROXIDASE, GPX; AND GLUCOSE-6-PHOSPHATE DEHYDROGENASE, G6DP) AND MARKERS OF OXIDATIVE DAMAGE (ADVANCED OXIDATION PROTEIN PRODUCTS, AOPP; LIPID PEROXIDATION, LPO). ADDITIONALLY, INFLAMMATORY MARKER LEVELS (IL-1, IL-6, IL-18, AND TNF-ALPHA), C-MIR-21, AND C-MIR-126 EXPRESSION WERE ANALYZED. T2DM PATIENTS SHOWED THE HIGHEST OXIDATIVE DAMAGE WITH INCREASED GSSG/GSH RATIOS, LPO, AND AOPP LEVELS. IN BOTH DIABETIC GROUPS, WE FOUND THAT DIMINISHED SOD ACTIVITY WAS ACCOMPANIED BY INCREASED CAT AND DECREASED GRD AND G6PD ACTIVITIES. DIABETIC PATIENTS PRESENTED WITH INCREASED RELATIVE EXPRESSION OF C-MIR-21 AND DECREASED RELATIVE EXPRESSION OF C-MIR-126. OVERALL, C-MIR-21, SOD, CAT, AND IL-6 HAD HIGH PREDICTIVE VALUES FOR DIABETES DIAGNOSES. FINALLY, OUR DATA DEMONSTRATED THAT IL-6 EXHIBITED PREDICTIVE VALUE FOR VC DEVELOPMENT IN THE STUDIED POPULATION. MOREOVER, C-MIR-21 AND C-MIR-126, ALONG WITH GPX AND AOPP LEVELS, SHOULD BE CONSIDERED POSSIBLE MARKERS FOR VC DEVELOPMENT IN FUTURE STUDIES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3   447  47 APABETALONE LOWERS SERUM ALKALINE PHOSPHATASE AND IMPROVES CARDIOVASCULAR RISK IN PATIENTS WITH CARDIOVASCULAR DISEASE. BACKGROUND AND AIMS: IN PATIENTS WITH CARDIOVASCULAR DISEASE, CONSIDERABLE RESIDUAL RISK REMAINS DESPITE EVIDENCE-BASED SECONDARY PREVENTION MEASURES. ALKALINE PHOSPHATASE (ALP) HAS BEEN SUGGESTED AS A MODIFIABLE CARDIOVASCULAR RISK FACTOR. WE SOUGHT TO DETERMINE WHETHER CARDIOVASCULAR RISK REDUCTION BY THE BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEIN INHIBITOR APABETALONE IS ASSOCIATED WITH THE CONCOMITANT LOWERING OF SERUM ALP. METHODS: IN A POST-HOC ANALYSIS OF 795 PATIENTS WITH ESTABLISHED CORONARY HEART DISEASE AND STATIN TREATMENT, WHO PARTICIPATED IN PHASE 2 PLACEBO-CONTROLLED TRIALS OF APABETALONE, WE DETERMINED THE EFFECT OF ASSIGNED TREATMENT FOR UP TO 24 WEEKS ON THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) AND SERUM ALP. RESULTS: BASELINE ALP (MEDIAN 72 U/L) PREDICTED MACE (DEATH, NON-FATAL MYOCARDIAL INFARCTION, CORONARY REVASCULARIZATION, OR HOSPITALIZATION FOR CARDIOVASCULAR CAUSES), INDEPENDENT OF HIGH-SENSITIVITY C-REACTIVE PROTEIN (HSCRP), SEX, AGE, RACE, STUDY, CARDIOVASCULAR RISK FACTORS, CHRONIC KIDNEY DISEASE (CKD), LIVER FUNCTION MARKERS AND TREATMENT ALLOCATION (HAZARD RATIO [HR] PER STANDARD DEVIATION [SD] 1.6, 95% CI 1.19-2.16, P = 0.002). MEAN PLACEBO-CORRECTED DECREASES IN ALP FROM BASELINE WERE 9.2% (P < 0.001) AFTER 12-14 WEEKS AND 7.7% (P < 0.001) AFTER 24-26 WEEKS OF APABETALONE TREATMENT. IN THE APABETALONE GROUP, A 1-SD REDUCTION IN ALP WAS ASSOCIATED WITH A HR FOR MACE OF 0.64 (95% CI 0.46-0.90, P = 0.009). CONCLUSIONS: SERUM ALP PREDICTS RESIDUAL CARDIOVASCULAR RISK, INDEPENDENT OF HSCRP, ESTABLISHED CARDIOVASCULAR RISK FACTORS AND CKD, IN PATIENTS WITH CARDIOVASCULAR DISEASE ON STATIN TREATMENT. APABETALONE LOWERS SERUM ALP, WHICH WAS ASSOCIATED WITH A LOWER RISK OF CARDIOVASCULAR EVENTS. WHETHER THE BENEFICIAL CARDIOVASCULAR EFFECTS OF APABETALONE ARE CAUSALLY RELATED TO ALP REDUCTION REMAINS UNDETERMINED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4   448  39 APABETALONE MEDIATED EPIGENETIC MODULATION IS ASSOCIATED WITH FAVORABLE KIDNEY FUNCTION AND ALKALINE PHOSPHATASE PROFILE IN PATIENTS WITH CHRONIC KIDNEY DISEASE. BACKGROUND/AIMS: THE ASSOCIATION BETWEEN SERUM ALKALINE PHOSPHATASE (ALP) WITH ADVERSE CARDIOVASCULAR OUTCOMES, IN CHRONIC KIDNEY DISEASE (CKD) PATIENTS HAS PREVIOUSLY BEEN REPORTED AND MAY BE A RESULT OF INCREASED VASCULAR CALCIFICATION AND INFLAMMATION. HERE WE REPORT, FOR THE FIRST TIME, THE EFFECTS OF PHARMACOLOGIC EPIGENETIC MODULATION ON LEVELS OF ALP AND KIDNEY FUNCTION VIA A NOVEL ORAL SMALL MOLECULE BET INHIBITOR, APABETALONE, IN CKD PATIENTS. METHODS: A POST-HOC ANALYSIS EVALUATED PATIENTS WITH ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) <60 ML/MIN/1.73M2, WHO PARTICIPATED IN THE APABETALONE PHASE 2 RANDOMIZED CONTROLLED TRIALS (SUSTAIN AND ASSURE). 48 CKD SUBJECTS WITH A HISTORY OF CARDIOVASCULAR DISEASE (CVD) WERE TREATED WITH 100MG TWICE-DAILY OF 24 AND 26 WEEKS OF APABETALONE OR PLACEBO. ALP AND EGFR WERE MEASURED PRIOR TO RANDOMIZATION AND AT FINAL VISITS. RESULTS: PATIENTS WHO RECEIVED APABETALONE (N=35) VERSUS PLACEBO (N=13) OVER 6 MONTHS SHOWED SIGNIFICANTLY (P=0.02) LOWERED SERUM ALP -14.0% (P<0.0001 VERSUS BASELINE) VERSUS -6.3% (P=0.9 VERSUS BASELINE). THE EGFR IN THE APABETALONE GROUP INCREASED BY 3.4% (1.7 ML/MIN/1.73 M2) (P=0.04 VERSUS BASELINE) AND DECREASED BY 5.8% (2.9 ML/MIN/1.73 M2) (P=0.6 VERSUS BASELINE) IN THE PLACEBO GROUP. APABETALONE WAS WELL TOLERATED. CONCLUSION: A POST-HOC ANALYSIS OF CKD SUBJECTS FROM THE SUSTAIN AND ASSURE RANDOMIZED CONTROLLED TRIALS DEMONSTRATED FAVORABLE EFFECTS OF APABETALONE ON ALP AND EGFR, AND GENERATED THE HYPOTHESIS THAT EPIGENETIC MODULATION BY BET INHIBITION MAY POTENTIALLY OFFER A NOVEL THERAPEUTIC STRATEGY TO TREAT CVD AND PROGRESSIVE KIDNEY FUNCTION LOSS IN CKD PATIENTS. THIS IS BEING EXAMINED IN THE PHASE III TRIAL BETONMACE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  1785  31 EFFECT OF APABETALONE ON CARDIOVASCULAR EVENTS IN DIABETES, CKD, AND RECENT ACUTE CORONARY SYNDROME: RESULTS FROM THE BETONMACE RANDOMIZED CONTROLLED TRIAL. BACKGROUND AND OBJECTIVES: CKD AND TYPE 2 DIABETES MELLITUS INTERACT TO INCREASE THE RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (I.E., CARDIOVASCULAR DEATH, NONFATAL MYOCARDIAL INFARCTION, OR STROKE) AND CONGESTIVE HEART FAILURE. A MALADAPTIVE EPIGENETIC RESPONSE MAY BE A CARDIOVASCULAR RISK DRIVER AND AMENABLE TO MODIFICATION WITH APABETALONE, A SELECTIVE MODULATOR OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN TRANSCRIPTION SYSTEM. WE EXAMINED THIS QUESTION IN A PRESPECIFIED ANALYSIS OF BETONMACE, A PHASE 3 TRIAL. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BETONMACE WAS AN EVENT-DRIVEN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING EFFECTS OF APABETALONE VERSUS PLACEBO ON MAJOR ADVERSE CARDIOVASCULAR EVENTS AND HEART FAILURE HOSPITALIZATIONS IN 2425 PARTICIPANTS WITH TYPE 2 DIABETES AND A RECENT ACUTE CORONARY SYNDROME, INCLUDING 288 PARTICIPANTS WITH CKD WITH EGFR <60 ML/MIN PER 1.73 M(2) AT BASELINE. THE PRIMARY END POINT IN BETONMACE WAS THE TIME TO THE FIRST MAJOR ADVERSE CARDIOVASCULAR EVENT, WITH A SECONDARY END POINT OF TIME TO HOSPITALIZATION FOR HEART FAILURE. RESULTS: MEDIAN FOLLOW-UP WAS 27 MONTHS (INTERQUARTILE RANGE, 20-32 MONTHS). IN PARTICIPANTS WITH CKD, APABETALONE COMPARED WITH PLACEBO WAS ASSOCIATED WITH FEWER MAJOR ADVERSE CARDIOVASCULAR EVENTS (13 EVENTS IN 124 PATIENTS [11%] VERSUS 35 EVENTS IN 164 PATIENTS [21%]; HAZARD RATIO, 0.50; 95% CONFIDENCE INTERVAL, 0.26 TO 0.96) AND FEWER HEART FAILURE-RELATED HOSPITALIZATIONS (THREE HOSPITALIZATIONS IN 124 PATIENTS [3%] VERSUS 14 HOSPITALIZATIONS IN 164 PATIENTS [9%]; HAZARD RATIO, 0.48; 95% CONFIDENCE INTERVAL, 0.26 TO 0.86). IN THE NON-CKD GROUP, THE CORRESPONDING HAZARD RATIO VALUES WERE 0.96 (95% CONFIDENCE INTERVAL, 0.74 TO 1.24) FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND 0.76 (95% CONFIDENCE INTERVAL, 0.46 TO 1.27) FOR HEART FAILURE-RELATED HOSPITALIZATION. INTERACTION OF CKD ON TREATMENT EFFECT WAS P=0.03 FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND P=0.12 FOR HEART FAILURE-RELATED HOSPITALIZATION. PARTICIPANTS WITH CKD SHOWED SIMILAR NUMBERS OF ADVERSE EVENTS, REGARDLESS OF RANDOMIZATION TO APABETALONE OR PLACEBO (119 [73%] VERSUS 88 [71%] PATIENTS), AND THERE WERE FEWER SERIOUS ADVERSE EVENTS (29% VERSUS 43%; P=0.02) IN THE APABETALONE GROUP. CONCLUSIONS: APABETALONE MAY REDUCE THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH CKD AND TYPE 2 DIABETES WHO HAVE A HIGH BURDEN OF CARDIOVASCULAR DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6   403  51 ANALYSIS OF EPIGENETIC AGE ACCELERATION AND HEALTHY LONGEVITY AMONG OLDER US WOMEN. IMPORTANCE: ACCELERATED BIOLOGICAL AGING IS ASSOCIATED WITH DECREASED PHYSICAL CAPABILITY AND COGNITIVE FUNCTIONING, WHICH ARE ASSOCIATED WITH INCREASED RISK OF MORBIDITY AND MORTALITY. OBJECTIVE: WE INVESTIGATED ASSOCIATIONS BETWEEN EPIGENETIC AGE ACCELERATION (EAA), A BIOMARKER ASSOCIATED WITH AGING, AND HEALTHY LONGEVITY AMONG OLDER WOMEN. DESIGN, SETTING, AND PARTICIPANTS: THIS COHORT STUDY WAS A SECONDARY ANALYSIS OF PARTICIPANTS IN THE WOMEN'S HEALTH INITIATIVE (WHI) WHO WERE ELIGIBLE TO SURVIVE TO AGE 90 YEARS BY SEPTEMBER 30, 2020. PARTICIPANTS WERE LOCATED IN MULTIPLE CENTERS. THIS STUDY WAS RESTRICTED TO WOMEN WITH GENOME-WIDE DNA METHYLATION DATA, GENERATED FROM BASELINE BLOOD SAMPLES WITHIN 3 WHI ANCILLARY STUDIES. MEDIAN (IQR) FOLLOW-UP TIMES FROM BASELINE WERE 21.6 (19.6-22.9) YEARS AND 21.4 (19.8-22.7) YEARS FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH AND WITHOUT INTACT MOBILITY, RESPECTIVELY, AND 13.2 (8.8-16.7) FOR WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. DATA WERE ANALYZED FROM DECEMBER 2020 TO JULY 2021. EXPOSURES: EAA WAS ESTIMATED USING 4 ESTABLISHED "CLOCKS": HORVATH PANTISSUE, HANNUM, PHENO, AND GRIM. MAIN OUTCOMES AND MEASURES: USING MULTINOMIAL LOGISTIC REGRESSION, ODDS RATIOS (ORS) AND 95% CIS WERE ESTIMATED FOR 3 HEALTHY LONGEVITY OUTCOMES FOR EACH CLOCK: SURVIVAL TO AGE 90 YEARS WITH INTACT MOBILITY, SURVIVAL TO AGE 90 YEARS WITHOUT INTACT MOBILITY, AND NO SURVIVAL TO AGE 90 YEARS. RESULTS: AMONG 1813 WOMEN, THERE WERE 464 WOMEN (MEAN [SD] AGE AT BASELINE, 71.6 [3.5] YEARS) WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTIONING, 420 WOMEN (MEAN [SD] AGE AT BASELINE, 71.3 [3.2] YEARS) WHO SURVIVED TO AGE 90 YEARS WITHOUT INTACT MOBILITY AND COGNITIVE FUNCTIONING, AND 929 WOMEN (MEAN [SD] AGE AT BASELINE, 70.2 [3.4] YEARS) WHO DID NOT SURVIVE TO AGE 90 YEARS. WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION WERE HEALTHIER AT BASELINE COMPARED WITH WOMEN WHO SURVIVED WITHOUT THOSE OUTCOMES OR WHO DID NOT SURVIVE TO AGE 90 YEARS (EG, 143 WOMEN [30.8%] VS 101 WOMEN [24.0%] AND 202 WOMEN [21.7%] WITH 0 CHRONIC CONDITIONS). THE ODDS OF SURVIVING TO AGE 90 YEARS WITH INTACT MOBILITY WERE LOWER FOR EVERY 1 SD INCREASE IN EAA COMPARED WITH THOSE WHO DID NOT SURVIVE TO AGE 90 YEARS AS MEASURED BY AGEACCELHORVATH (OR, 0.82; 95% CI, 0.69-0.96; P = .01), AGEACCELHANNUM (OR, 0.67; 95% CI, 0.56-0.80; P < .001), AGEACCELPHENO (OR, 0.60; 95% CI, 0.51-0.72; P < .001), AND AGEACCELGRIM (OR, 0.68; 95% CI, 0.55-0.84; P < .001). ORS WERE SIMILAR FOR WOMEN WHO SURVIVED TO AGE 90 YEARS WITH INTACT MOBILITY AND COGNITIVE FUNCTION (EG, AGEACCELHORVATH: OR PER 1 SD INCREASE IN EAA, 0.83; 95% CI, 0.71-0.98; P = .03) COMPARED WITH WOMEN WHO DID NOT SURVIVE TO AGE 90 YEARS. CONCLUSIONS AND RELEVANCE: THESE FINDINGS SUGGEST THAT EAA MAY BE A VALID BIOMARKER ASSOCIATED WITH HEALTHY LONGEVITY AMONG OLDER WOMEN AND MAY BE USED FOR RISK STRATIFICATION AND RISK ESTIMATION OF FUTURE FUNCTIONAL AND COGNITIVE AGING. OUTCOMES SUGGEST THAT FUTURE STUDIES MAY FOCUS ON THE POTENTIAL FOR PUBLIC HEALTH INTERVENTIONS TO COUNTERACT EAA AND ITS ASSOCIATION WITH POOR HEALTH OUTCOMES TO LOWER DISEASE BURDEN WHILE INCREASING LONGEVITY.	2022	

7  3046  34 GENOME-WIDE ANALYSIS OF DNA METHYLATION IDENTIFIES S100A13 AS AN EPIGENETIC BIOMARKER IN INDIVIDUALS WITH CHRONIC (>/= 30 YEARS) TYPE 2 DIABETES WITHOUT DIABETIC RETINOPATHY. BACKGROUND: THIS STUDY AIMED TO DETERMINE THE EPIGENETIC BIOMARKERS OF DIABETIC RETINOPATHY (DR) IN SUBJECTS WITH TYPE 2 DIABETES MELLITUS (T2DM). THIS RETROSPECTIVE STUDY IS BASED ON THE SHANGHAI XINJING COMMUNITY PREVENTION AND TREATMENT ADMINISTRATIVE SYSTEM OF CHRONIC DISEASES. THE SUBJECTS ENROLLED HEREIN WERE T2DM PATIENTS WHO HAD UNDERGONE LONG-TERM FOLLOW-UP EVALUATION IN THE SYSTEM. TWO CONSECUTIVE STUDIES WERE CONDUCTED. IN THE DISCOVERY COHORT, AMONG 19 SUBJECTS WHO HAD DEVELOPED DR WITH A DM DURATION < 3 YEARS AND 21 SUBJECTS WITHOUT DR > 30 YEARS AFTER BEING DIAGNOSED WITH DM, AN INFINIUM HUMAN METHYLATION 850 BEADCHIP WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION REGIONS (DMRS) AND DIFFERENTIAL METHYLATION SITES (DMSS). THE FUNCTION OF THE GENES WAS ASSESSED THROUGH KEGG ENRICHMENT ANALYSIS, GENE ONTOLOGY (GO) ANALYSIS, AND PATHWAY NETWORK ANALYSIS. IN THE REPLICATION COHORT, 87 DR PATIENTS WITH A SHORT DM DURATION AND 89 PATIENTS WITHOUT DR OVER A DM DURATION > 20 YEARS WERE COMPARED TO ASSESS THE ASSOCIATION BETWEEN DMSS AND DR UPON PYROSEQUENCING. RESULTS: A TOTAL OF 34 DMRS WERE IDENTIFIED. GENES CONTAINING DMSS WITH THE TOP 5 HIGHEST BETA VALUE DIFFERENCES BETWEEN DR AND NON-DR PARTICIPANTS WERE LOCATED ON CHROMOSOME 1 AND WERE PRESENT IN THE S100A13 GENE, WHICH WAS ASSOCIATED WITH 71 GO TERMS. TWO S100A13 GENE SITES, I.E., CG02873163 AND CG11343894, DISPLAYED A GOOD CORRELATION WITH DR ON PYROSEQUENCING. CONCLUSIONS: DMSS IN THE S100A13 GENE MAY BE POTENTIAL BIOMARKERS OF DR.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8  4249  39 METHYLATION-BASED BIOLOGICAL AGE AND BREAST CANCER RISK. BACKGROUND: AGE IS ONE OF THE STRONGEST PREDICTORS OF CANCER, CHRONIC DISEASE, AND MORTALITY, BUT BIOLOGICAL RESPONSES TO AGING DIFFER AMONG PEOPLE. EPIGENETIC DNA MODIFICATIONS HAVE BEEN USED TO ESTIMATE "BIOLOGICAL AGE," WHICH MAY BE A USEFUL PREDICTOR OF DISEASE RISK. WE TESTED THIS HYPOTHESIS FOR BREAST CANCER. METHODS: USING A CASE-COHORT APPROACH, WE MEASURED BASELINE BLOOD DNA METHYLATION OF 2764 WOMEN ENROLLED IN THE SISTER STUDY, 1566 OF WHOM SUBSEQUENTLY DEVELOPED BREAST CANCER AFTER AN AVERAGE OF 6 YEARS. USING THREE PREVIOUSLY ESTABLISHED METHYLATION-BASED "CLOCKS" (HANNUM, HORVATH, AND LEVINE), WE DEFINED BIOLOGICAL AGE ACCELERATION FOR EACH WOMAN BY COMPARING HER ESTIMATED BIOLOGICAL AGE WITH HER CHRONOLOGICAL AGE. HAZARD RATIOS AND 95% CONFIDENCE INTERVALS FOR BREAST CANCER RISK WERE ESTIMATED USING COX REGRESSION MODELS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: EACH OF THE THREE CLOCKS SHOWED THAT BIOLOGICAL AGE ACCELERATION WAS STATISTICALLY SIGNIFICANTLY ASSOCIATED WITH INCREASED RISK OF DEVELOPING BREAST CANCER (5-YEAR AGE ACCELERATION, HANNUM'S CLOCK: HAZARD RATIO [HR] = 1.10, 95% CONFIDENCE INTERVAL [CI] = 1.00 TO 1.21, P = .04; HORVATH'S CLOCK: HR = 1.08, 95% CI = 1.00 TO 1.17, P = .04; LEVINE'S CLOCK: HR = 1.15, 95% CI = 1.07 TO 1.23, P < .001). FOR LEVINE'S CLOCK, EACH 5-YEAR ACCELERATION IN BIOLOGICAL AGE CORRESPONDED WITH A 15% INCREASE IN BREAST CANCER RISK. ALTHOUGH BIOLOGICAL AGE MAY ACCELERATE WITH MENOPAUSAL TRANSITION, AGE ACCELERATION IN PREMENOPAUSAL WOMEN INDEPENDENTLY PREDICTED BREAST CANCER. CASE-ONLY ANALYSIS SUGGESTED THAT, AMONG WOMEN WHO DEVELOP BREAST CANCER, INCREASED AGE ACCELERATION IS ASSOCIATED WITH INVASIVE CANCER (ODDS RATIO FOR INVASIVE = 1.09, 95% CI = 0.98 TO 1.22, P = .10). CONCLUSIONS: DNA METHYLATION-BASED MEASURES OF BIOLOGICAL AGE MAY BE IMPORTANT PREDICTORS OF BREAST CANCER RISK.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9  1797  36 EFFECT OF HELICOBACTER PYLORI ERADICATION ON GASTRIC PRECANCEROUS LESIONS: A SYSTEMATIC REVIEW AND META-ANALYSIS. BACKGROUND: THE QUESTION OF WHETHER ERADICATION OF HELICOBACTER PYLORI (HP) CAN REVERSE GASTRIC PRECANCEROUS LESIONS, INCLUDING INTESTINAL METAPLASIA, REMAINS UNCERTAIN, LEADING TO ONGOING DEBATE. THEREFORE, A META-ANALYSIS WAS PERFORMED TO EVALUATE THE EFFECT OF HP ERADICATION ON GASTRIC PRECANCEROUS LESIONS. MATERIALS AND METHODS: PUBMED, EMBASE, COCHRANE LIBRARY, WEB OF SCIENCE, SCOPUS DATABASE, AND CLINICALTRIALS.GOV WERE SYSTEMATICALLY SEARCHED FROM INCEPTION TO APRIL 2023 FOR STUDIES THAT EXPLORED THE IMPACT OF HP ERADICATION ON GASTRIC PRECANCEROUS LESIONS. RISK RATIOS (RRS) AND THEIR 95% CONFIDENCE INTERVALS (95% CIS) WERE SELECTED AS THE EFFECT SIZE. WE USED THE RANDOM-EFFECTS MODEL TO ASSESS POOLED DATA. WE ALSO PERFORMED QUALITY ASSESSMENTS, SUBGROUP ANALYSES, AND SENSITIVITY ANALYSES. RESULTS: FIFTEEN STUDIES WERE INCLUDED. COMPARED WITH PLACEBO, HP ERADICATION COULD SIGNIFICANTLY PREVENT THE PROGRESSION OF GASTRIC PRECANCEROUS LESIONS (RR = 0.87, 95% CI: 0.81-0.94, P < 0.01) AND REVERSE THEM (RR = 1.32, 95% CI: 1.17-1.50, P < 0.01). THEN, SPECIFIC PRECANCEROUS LESIONS WERE FURTHER EXPLORED. THE PROGRESSION OF INTESTINAL METAPLASIA WAS SIGNIFICANTLY PREVENTED BY HP ERADICATION COMPARED TO PLACEBO OR NO TREATMENT (RR = 0.80, 95% CI: 0.69-0.94, P < 0.01). MOREOVER, COMPARED WITH PLACEBO OR NO TREATMENT, HP ERADICATION ALSO IMPROVED CHRONIC ATROPHIC GASTRITIS (RR = 1.84, 95% CI: 1.30-2.61, P < 0.01) AND INTESTINAL METAPLASIA (RR = 1.41, 95% CI: 1.15-1.73, P < 0.01). HOWEVER, IN TERMS OF PREVENTING DYSPLASIA PROGRESSION (RR = 0.86, 95% CI: 0.37-2.00) AND IMPROVING DYSPLASIA (RR = 0.89, 95% CI: 0.47-1.70), HP ERADICATION HAD NO ADVANTAGE COMPARED TO PLACEBO OR NO TREATMENT. CONCLUSIONS: HP ERADICATION THERAPY COULD PREVENT THE PROGRESSION OF GASTRIC PRECANCEROUS LESIONS AND REVERSE THEM. NOTABLY, INTESTINAL METAPLASIA CAN BE REVERSED, BUT THIS MAY ONLY BE APPROPRIATE FOR PATIENTS WITH EPIGENETIC ALTERATIONS AND MILDER LESIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10   525  33 ASSOCIATIONS OF BODY COMPOSITION AND PHYSICAL ACTIVITY LEVEL WITH MULTIPLE MEASURES OF EPIGENETIC AGE ACCELERATION. EPIGENETIC CLOCKS USE DNA METHYLATION TO ESTIMATE BIOLOGICAL AGE. WHETHER BODY COMPOSITION AND PHYSICAL ACTIVITY ARE ASSOCIATED WITH THESE CLOCKS IS NOT WELL UNDERSTOOD. USING BLOOD SAMPLES COLLECTED AT ENROLLMENT (2003-2009) FROM 2,758 WOMEN IN THE US NATIONWIDE SISTER STUDY, WE CALCULATED 6 EPIGENETIC AGE ACCELERATION METRICS USING 4 EPIGENETIC CLOCKS (HANNUM, HORVATH, PHENOAGE, GRIMAGE). RECREATIONAL PHYSICAL ACTIVITY WAS SELF-REPORTED, AND ADIPOSITY MEASURES WERE ASSESSED BY TRAINED MEDICAL EXAMINERS (BODY MASS INDEX (BMI), WAIST-TO-HIP RATIO (WTH), WAIST CIRCUMFERENCE). IN CROSS-SECTIONAL ANALYSES, ALL ADIPOSITY MEASURES WERE ASSOCIATED WITH EPIGENETIC AGE ACCELERATION. THE STRONGEST ASSOCIATION WAS FOR BMI AND PHENOAGE, A MEASURE OF BIOLOGICAL AGE THAT CORRELATES WITH CHRONIC DISEASE (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 3.15 YEARS, 95% CONFIDENCE INTERVAL (CI): 2.41, 3.90; P FOR TREND < 0.001). IN A MUTUAL-ADJUSTMENT MODEL, BOTH WERE ASSOCIATED WITH PHENOAGE AGE ACCELERATION (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 2.69 YEARS, 95% CI: 1.90, 3.48; P FOR TREND < 0.001; QUARTILE 4 VS.1 WTH, BETA = 1.00 YEARS, 95% CI: 0.34, 1.65; P FOR TREND < 0.008). AFTER ADJUSTMENT, PHYSICAL ACTIVITY WAS ASSOCIATED ONLY WITH GRIMAGE (QUARTILE 4 VS. 1, BETA = -0.42 YEARS, 95% CI: -0.70, -0.14; P FOR TREND = 0.001). PHYSICAL ACTIVITY ATTENUATED THE WAIST CIRCUMFERENCE ASSOCIATIONS WITH PHENOAGE AND GRIMAGE. EXCESS ADIPOSITY WAS ASSOCIATED WITH EPIGENETIC AGE ACCELERATION; PHYSICAL ACTIVITY MIGHT ATTENUATE ASSOCIATIONS WITH WAIST CIRCUMFERENCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11  3456  30 HYPOMETHYLATION OF IL1RN AND NFKB1 GENES IS LINKED TO THE DYSBALANCE IN IL1BETA/IL-1RA AXIS IN FEMALE PATIENTS WITH TYPE 2 DIABETES MELLITUS. INFLAMMATION HAS RECEIVED CONSIDERABLE ATTENTION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS (T2DM). SUPPORTING THIS CONCEPT, ENHANCED EXPRESSION OF INTERLEUKIN (IL)-1BETA AND INCREASED INFILTRATION OF MACROPHAGES ARE OBSERVED IN PANCREATIC ISLETS OF PATIENTS WITH T2DM. ALTHOUGH IL-1 RECEPTOR ANTAGONIST (IL-1RA) PLAYS A MAJOR ROLE IN CONTROLLING OF IL-1BETA-MEDIATED INFLAMMATION, ITS COUNTERACTION EFFECTS AND EPIGENETIC ALTERATIONS IN T2DM ARE LESS STUDIED. THUS, WE AIMED TO ANALYZE THE DNA METHYLATION STATUS IN IL1RN, RELA (P65) AND NFKB1 (P50) GENES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM TREATED T2DM PATIENTS (N = 35) AND AGE-/SEX- MATCHED HEALTHY CONTROLS (N = 31). PRODUCTION OF IL-1BETA AND IL-1RA WAS ANALYZED IN PLASMA AND SUPERNATANTS FROM LPS-INDUCED PBMCS. IMMUNOMODULATORY EFFECTS OF IL-1BETA AND IL-1RA WERE STUDIED ON THP-1 CELLS. AVERAGE DNA METHYLATION LEVEL OF IL1RN AND NFKB1 GENE PROMOTERS WAS SIGNIFICANTLY DECREASED IN T2DM PATIENTS IN COMPARISON WITH HEALTHY CONTROLS (P< 0.05), WHICH WAS ASSOCIATED WITH THE INCREASED IL-1RA (P< 0.001) AND IL-1BETA (P = 0.039) PLASMA LEVELS IN T2DM PATIENTS. NEGATIVE ASSOCIATION BETWEEN AVERAGE METHYLATION OF IL1RN GENE AND IL-1RA PLASMA LEVELS WERE OBSERVED IN FEMALE T2DM PATIENTS. METHYLATION OF NFKB1 GENE WAS NEGATIVELY CORRELATED WITH IL-1RA LEVELS IN THE PATIENTS AND POSITIVELY WITH IL-1BETA LEVELS IN FEMALE PATIENTS. LPS-STIMULATED PBMCS FROM FEMALE PATIENTS FAILED TO RAISE IL-1BETA PRODUCTION, WHILE THE CELLS FROM HEALTHY FEMALES INCREASED IL-1BETA PRODUCTION IN COMPARISON WITH UNSTIMULATED CELLS (P< 0.001). TAKEN TOGETHER, THE FINDINGS SUGGEST THAT HYPOMETHYLATION OF IL1RN AND NFKB1 GENE PROMOTERS MAY PROMOTE THE INCREASED IL-1BETA/IL-1RA PRODUCTION AND REGULATE CHRONIC INFLAMMATION IN T2DM. FURTHER STUDIES ARE NECESSARY TO ELUCIDATE THE CAUSAL DIRECTION OF THESE ASSOCIATIONS AND POTENTIAL ROLE OF IL-1RA IN ANTI-INFLAMMATORY PROCESSES IN TREATED PATIENTS WITH T2DM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12  4349  26 MIR-155 AND MIR-122 EXPRESSION OF SPERMATOZOA IN OBESE SUBJECTS. OBESITY IS CHARACTERIZED BY MILD CHRONIC INFLAMMATION THAT IS LINKED WITH IMPAIRED IRON HOMEOSTASIS. STUDIES IN HUMAN AND MURINE SHOW THAT THERE IS A TRANSGENERATIONAL EPIGENETIC INHERITANCE VIA THE GAMETES IN OBESITY; HOWEVER, THERE IS LITTLE INFORMATION ON CHANGES IN THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION AND IRON HOMEOSTASIS IN SPERMATOZOA FROM OBESE SUBJECTS. THE PRESENT STUDY INVESTIGATED THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION (MIR-21 Y MIR-155) AND IRON NUTRITION (MIR-122 AND MIR-200B) IN PLASMA, PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND SPERMATOZOA FROM NORMOZOOSPERMIC CONTROLS (CN; N = 17; BMI: 24.6 +/- 2.0) AND OBESE (OB; N = 17; BMI: 32.6 +/- 4.4) MEN. TO DETERMINE THE INFLAMMATION LEVELS, WE MEASURED IL-6, TNF-ALPHA, AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP1) BY MAGNETIC LUMINEX((R)) ASSAY. MRNA EXPRESSION OF IL6, TNF-ALPHA, AND HEPCIDIN (HAMP) IN PBMC WERE EVALUATED BY RT-QPCR. THE ANALYSIS OF MICRORNAS WAS PERFORMED USING THE TAQMAN((R)) ASSAYS. THE IRON CONTENT IN PBMC, SEMINAL PLASMA, AND SPERMATOZOA WAS DETERMINED BY INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY (ICP-MS). HIGH SERUM IL6, TNF-ALPHA, AND MCP1 LEVELS WERE OBSERVED IN OB GROUP (P < 0.05). GENE EXPRESSION ANALYSIS SHOWED AN INCREASED ABUNDANCE RELATIVE OF TNF-ALPHA (P = 0.018), HAMP (P = 0.03), AND IL6 (P = 0.02) IN PBMC FROM OBESE SUBJECTS. ALSO, WE OBSERVED HIGH LEVELS OF SERUM FERRITIN (P = 0.03), IRON CONTENT IN SEMINAL PLASMA (P = 0.04), AND SPERMATOZOA (P = 0.002), BUT LOWER SERUM FE (P = 0.007) IN OBESE SUBJECTS. IN THE OB GROUP, A HIGH EXPRESSION OF MIR-155 (P = 0.02) AND MIR-21 (P = 0.03) WAS OBSERVED IN PBMC AND MIR-122 (P = 0.03) IN PLASMA. IN SPERM, BOTH MIR-155 (P = 0.004) AND MIR-122 (P = 0.028) WERE HIGH IN THE OB GROUP. OUR RESULTS SHOWED THAT OBESE SUBJECTS HAVE INCREASED EXPRESSIONS OF MIR-155 AND MIR-122, TWO MICRORNAS THAT WERE PREVIOUSLY RELATED WITH INFLAMMATION AND IRON METABOLISM, RESPECTIVELY, AT BOTH THE SYSTEMIC AND SPERM LEVELS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13   659  34 BLOOD GLOBAL DNA METHYLATION IS DECREASED IN NON-SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS. BACKGROUND: ALTERATIONS IN GLOBAL DNA METHYLATION HAVE BEEN ASSOCIATED WITH OXIDATIVE STRESS (OS). SINCE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY INCREASED OXIDATIVE STRESS WE AIMED TO EVALUATE THE LEVELS OF GLOBAL DNA METHYLATION IN THIS PATIENT GROUP. METHODS: WE ASSESSED METHYLCYTOSINE (MCYT) LEVELS IN DNA FROM BLOOD COLLECTED IN 43 COPD PATIENTS (29 WITH MILD AND 14 WITH MODERATE DISEASE) AND 43 AGE- AND SEX-MATCHED HEALTHY CONTROLS. RESULTS: DNA METHYLATION WAS SIGNIFICANTLY LOWER IN COPD PATIENTS VS. CONTROLS (4.20 +/- 0.18% MCYT VS. 4.29 +/- 0.18% MCYT, P = 0.02). FURTHERMORE, DNA METHYLATION IN COPD PATIENTS WITH MODERATE DISEASE WAS SIGNIFICANTLY LOWER THAN THAT IN PATIENTS WITH MILD DISEASE (4.14 +/- 0.15% MCYT VS. 4.23 +/- 0.19% MCYT, P < 0.05). UNIVARIATE LOGISTIC REGRESSION ANALYSIS SHOWED THAT LOWER DNA METHYLATION LEVELS WERE ASSOCIATED WITH PRESENCE OF COPD (CRUDE OR = 0.06, 95% CI 0.00 TO 0.67, P = 0.023). THIS RELATIONSHIP REMAINED SIGNIFICANT AFTER ADJUSTING FOR SEVERAL CONFOUNDERS (OR 0.03, 95% CI 0.00 TO 0.67; P = 0.028). RECEIVER OPERATING CHARACTERISTICS (ROC) CURVE ANALYSIS DEMONSTRATED THE AREA UNDER THE CURVE OF MCYT WAS 0.646, WITH 46.6% SENSITIVITY AND 79.1% SPECIFICITY FOR PRESENCE OF COPD. CONCLUSIONS: THERE WERE NO SIGNIFICANT CORRELATIONS BETWEEN METHYLATION AND OS INDICES. THE PRESENCE AND SEVERITY OF COPD IS ASSOCIATED WITH PROGRESSIVELY LOWER DNA METHYLATION IN BLOOD. HOWEVER, THIS EPIGENETIC ALTERATION SEEMS INDEPENDENT OF OXIDATIVE STRESS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
14   974  39 CHRONIC OCCUPATIONAL EXPOSURE ENDURED BY TOBACCO FARMERS FROM BRAZIL AND ASSOCIATION WITH DNA DAMAGE. TOBACCO FARMING IS AN IMPORTANT ECONOMIC INCOME IN BRAZIL, ALTHOUGH IT HAS BEEN CHALLENGED AS REGARD THE OCCUPATIONAL EXPOSURE TO BOTH PESTICIDES AND NICOTINE ENDURED BY FARMERS. CHRONIC OCCUPATIONAL EXPOSURE TO COMPLEX MIXTURES CAN LEAD TO HEALTH HAZARDOUS. WE EXAMINED GENOMIC INSTABILITY AND EPIGENETIC CHANGES IN TOBACCO FARMERS OCCUPATIONALLY EXPOSED TO PESTICIDE MIXTURES AND NICOTINE AT TOBACCO FIELDS. DNA DAMAGE WAS ASSESSED BY ALKALINE COMET ASSAY IN BLOOD CELLS. GENOMIC DNA WAS ISOLATED, AND TELOMERE LENGTH WAS MEASURED USING QUANTITATIVE POLYMERASE CHAIN REACTION ASSAY. WE MEASURED 5-METHYL-2'-DEOXYCYTIDINE, A MARKER OF GLOBAL DNA METHYLATION, AND P16 PROMOTER METHYLATION. THE OXIDATIVE PROFILE WAS EVALUATED BY TROLOX EQUIVALENT ANTIOXIDANT CAPACITY AND LIPID PEROXIDATION (THIOBARBITURIC ACID REACTIVE SUBSTANCES) IN SERUM. EXPOSURE PARAMETERS, PLASMA COTININE AND INORGANIC ELEMENT LEVELS, WERE ALSO MEASURED. DNA DAMAGE WAS SIGNIFICANTLY ELEVATED FOR FARMERS IN RELATION TO UNEXPOSED GROUP (P < 0.001; MANN-WHITNEY TEST) AND POSITIVELY ASSOCIATED WITH YEARS OF EXPOSURE. INVERSE RELATIONSHIP BETWEEN DNA DAMAGE AND TOTAL EQUIVALENT ANTIOXIDANT ACTIVITY WAS DEMONSTRATED FOR EXPOSED AND UNEXPOSED GROUPS. EXPOSED GROUP SHOWED SIGNIFICANTLY SHORTER TELOMERES (P < 0.001; UNPAIRED T-TEST) AND DNA HYPOMETHYLATION (P < 0.001; UNPAIRED T-TEST), AS WELL AS P16 HYPERMETHYLATION (P = 0.003; MANN-WHITNEY TEST). LIPID PEROXIDATION WAS INCREASED FOR EXPOSED GROUP IN RELATION TO UNEXPOSED ONE (P = 0.02; MANN-WHITNEY TEST) AND PRESENTED A POSITIVE CORRELATION WITH GLOBAL DNA METHYLATION (P = 0.0264). FARMERS HAVE INCREASED PLASMA COTININE LEVELS (P < 0.001) AND INORGANIC ELEMENTS (PHOSPHORUS, SULPHUR AND CHLORINE) IN RELATION TO UNEXPOSED GROUP. ELEVATED OXIDATIVE STRESS LEVELS DUE TO CHRONIC OCCUPATIONAL PESTICIDE MIXTURES AND NICOTINE EXPOSURE IN TOBACCO FARMERS WERE ASSOCIATED WITH HIGHER DNA DAMAGE, SHORTER TELOMERES AND ALTERED DNA METHYLATION. TELOMERE-ACCELERATED ATTRITION DUE TO EXPOSURE MAY BE POTENTIAL INTERMEDIATE STEP BEFORE A DISEASE STATE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15  3592  42 IMPAIRED VASCULAR FUNCTION CONTRIBUTES TO EXERCISE INTOLERANCE IN CHRONIC KIDNEY DISEASE. BACKGROUND: EXERCISE INTOLERANCE IS AN IMPORTANT FEATURE IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) AND IS PROGNOSTIC FOR BOTH INCREASED MORBIDITY AND MORTALITY. LITTLE IS KNOWN ABOUT THE UNDERLYING MECHANISMS IN PREDIALYSIS CKD. THIS STUDY AIMED TO GAIN MORE INSIGHT INTO THE ROLE OF VASCULAR DYSFUNCTION IN THE EXERCISE INTOLERANCE OF PREDIALYSIS CKD. IN ADDITION, VASCULAR-RELATED MICRORNAS (MIRNAS)-AS EPIGENETIC REGULATORS OF EXERCISE CAPACITY-WERE ANALYSED. METHODS: SIXTY-THREE PATIENTS WITH CKD STAGES 1-5 AND 18 HEALTHY CONTROLS WERE INCLUDED. PEAK OXYGEN CONSUMPTION (VO(2)PEAK) WAS DETERMINED BY CARDIOPULMONARY EXERCISE TESTING, ENDOTHELIAL FUNCTION BY FLOW-MEDIATED DILATION (FMD) AND ARTERIAL STIFFNESS BY CAROTID-FEMORAL PULSE WAVE VELOCITY (PWV). PLASMA MIRNA LEVELS (MIR-21, MIR-126, MIR-146A, MIR-150 AND MIR-210) WERE QUANTIFIED BY QUANTITATIVE RT-PCR. RESULTS: VO(2)PEAK WAS ALREADY IMPAIRED IN MILD CKD (STAGES 1-3A) AND SIGNIFICANTLY CORRELATED WITH ESTIMATED GLOMERULAR FILTRATION RATE (EGFR; R = 0.525, P < 0.001). LIKEWISE, BOTH FMD AND PWV WERE SIGNIFICANTLY CORRELATED WITH EGFR (R = 0.319, P = 0.007 AND R = -0.365, P = 0.001, RESPECTIVELY). IN MULTIPLE REGRESSION ANALYSIS, PWV REMAINED ONE OF THE STRONGEST INDEPENDENT DETERMINANTS OF VO(2)PEAK (BETA = -0.301, P = 0.01). OF THE STUDIED MIRNA, CIRCULATING LEVELS OF MIR-146A AND MIR-150 CORRELATED WITH EGFR, PWV AND VO(2)PEAK, BUT THE ASSOCIATION WITH THE LATTER WAS LOST WHEN CORRECTING FOR PWV. CONCLUSIONS: ARTERIAL STIFFNESS CONTRIBUTES TO THE OBSERVED REDUCED AEROBIC CAPACITY IN PREDIALYSIS CKD, INDEPENDENT OF AGE, HAEMOGLOBIN LEVELS AND ENDOTHELIAL FUNCTION AND REPRESENTS A PROMISING THERAPEUTIC TARGET FOR IMPROVING EXERCISE CAPACITY IN THIS POPULATION. FUTURE WORK IS REQUIRED TO ELUCIDATE WHY HIGHER CIRCULATING LEVELS OF MIR-146A AND MIR-150 ARE ASSOCIATED WITH IMPAIRED RENAL FUNCTION AND INCREASED ARTERIAL STIFFNESS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16   401  36 ANALYSIS OF ABERRANT METHYLATION ON PROMOTER SEQUENCES OF TUMOR SUPPRESSOR GENES AND TOTAL DNA IN SPUTUM SAMPLES: A PROMISING TOOL FOR EARLY DETECTION OF COPD AND LUNG CANCER IN SMOKERS. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A DISORDER ASSOCIATED TO CIGARETTE SMOKE AND LUNG CANCER (LC). SINCE EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES (TSGS) ARE CLEARLY IMPORTANT IN THE DEVELOPMENT OF LC. IN THIS STUDY, WE HYPOTHESIZE THAT TOBACCO SMOKERS ARE SUSCEPTIBLE FOR METHYLATION IN THE PROMOTER REGION OF TSGS IN AIRWAY EPITHELIAL CELLS WHEN COMPARED WITH NON-SMOKER SUBJECTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE USEFULNESS OF DETECTION OF GENES PROMOTER METHYLATION IN SPUTUM SPECIMENS, AS A COMPLEMENTARY TOOL TO IDENTIFY LC BIOMARKERS AMONG SMOKERS WITH EARLY COPD. METHODS: WE DETERMINED THE AMOUNT OF DNA IN INDUCED SPUTUM FROM PATIENTS WITH COPD (N = 23), LC (N = 26), AS WELL AS IN HEALTHY SUBJECTS (CTR) (N = 33), USING A COMMERCIAL KIT FOR DNA PURIFICATION, FOLLOWED BY ABSORBANCE MEASUREMENT AT 260 NM. THE FREQUENCY OF CDKN2A, CDH1 AND MGMT PROMOTER METHYLATION IN THE SAME GROUPS WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP). THE FISHER'S EXACT TEST WAS EMPLOYED TO COMPARE FREQUENCY OF RESULTS BETWEEN DIFFERENT GROUPS. RESULTS: DNA CONCENTRATION WAS 7.4 AND 5.8 TIMES HIGHER IN LC AND COPD COMPARED TO THE (CTR) (P < 0.0001), RESPECTIVELY. METHYLATION STATUS OF CDKN2A AND MGMT WAS SIGNIFICANTLY HIGHER IN COPD AND LC PATIENTS COMPARED WITH CTR GROUP (P < 0.0001). FREQUENCY OF CDH1 METHYLATION ONLY SHOWED A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN LC PATIENTS AND CTR GROUP (P < 0.05). CONCLUSIONS: WE PROVIDE EVIDENCE THAT ABERRANT METHYLATION OF TSGS IN SAMPLES OF INDUCED SPUTUM IS A USEFUL TOOL FOR EARLY DIAGNOSTIC OF LUNG DISEASES (LC AND COPD) IN SMOKER SUBJECTS. VIRTUAL SLIDES: THE ABSTRACT MUST FINISH WITH THE FOLLOWING TEXT: VIRTUAL SLIDES THE VIRTUAL SLIDE(S) FOR THIS ARTICLE CAN BE FOUND HERE: HTTP://WWW.DIAGNOSTICPATHOLOGY.DIAGNOMX.EU/VS/1127865005664160.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  1956  42 EPIGENETIC AGE IN PERIPHERAL BLOOD AMONG CHILDREN, ADOLESCENT, AND ADULT SURVIVORS OF CHILDHOOD CANCER. IMPORTANCE: CERTAIN CANCER THERAPIES ARE RISK FACTORS FOR EPIGENETIC AGE ACCELERATION (EAA) AMONG SURVIVORS OF CHILDHOOD CANCER, AND EAA IS ASSOCIATED WITH CHRONIC HEALTH CONDITIONS (CHCS). HOWEVER, SMALL NUMBERS OF YOUNGER SURVIVORS (AGED <20 YEARS) PREVIOUSLY EVALUATED HAVE LIMITED THE ABILITY TO CALCULATE EAA AMONG THIS AGE GROUP. OBJECTIVE: TO EVALUATE THE CHANGE RATE OF EPIGENETIC AGE (EA) AND EAA IN YOUNGER COMPARED WITH OLDER SURVIVORS AND THE POSSIBLE ASSOCIATION OF EAA WITH EARLY-ONSET OBESITY (AGED <20 YEARS), SEVERITY/BURDEN OF CHCS, AND LATE MORTALITY (>5 YEARS FROM CANCER DIAGNOSIS). DESIGN, SETTING, AND PARTICIPANTS: STUDY PARTICIPANTS WERE FROM THE ST JUDE LIFETIME COHORT, INITIATED IN 2007 WITH ONGOING FOLLOW-UP. THE PRESENT STUDY WAS CONDUCTED FROM APRIL 17, 2022, TO MARCH 23, 2023. SURVIVORS IN THIS COHORT OF EUROPEAN ANCESTRY WITH DNA METHYLATION DATA WERE INCLUDED. CROSS-SECTIONAL ANNUAL CHANGES IN EA AND EAA WERE COMPARED ACROSS 5 DIFFERENT CHRONOLOGIC AGE GROUPS: AGE 0 TO 9 (CHILDREN), 10 TO 19 (ADOLESCENTS), 20 TO 34 (YOUNGER ADULTS), 35 TO 49 (MIDDLE-AGED ADULTS), AND GREATER THAN OR EQUAL TO 50 (OLDER ADULTS) YEARS. LOGISTIC REGRESSION EVALUATED THE ASSOCIATION BETWEEN EAA AND EARLY-ONSET OBESITY OR SEVERITY/BURDEN OF CHCS. COX PROPORTIONAL HAZARDS REGRESSION ASSESSED THE ASSOCIATION BETWEEN EAA AND LATE MORTALITY. MAIN OUTCOMES AND MEASURES: EARLY-ONSET OBESITY, SEVERITY/BURDEN OF CHCS (GRADED USING THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (GRADE 1, MILD; 2, MODERATE; 3, SEVERE/DISABLING; 4, LIFE-THREATENING) AND WERE COMBINED INTO HIGH VS LOW SEVERITY/BURDEN BASED ON FREQUENCY AND GRADE), AND LATE MORTALITY WERE THE OUTCOMES BASED ON FOLLOW-UP UNTIL APRIL 2020. EXPANDED DNA METHYLATION PROFILING INCREASED THE NUMBER OF SURVIVORS YOUNGER THAN 20 YEARS (N = 690). EPIGENETIC AGE WAS CALCULATED PRIMARILY USING THE LEVINE CLOCK, AND EAA WAS DERIVED FROM LEAST SQUARES REGRESSION OF EA AGAINST CHRONOLOGIC AGE AND WAS STANDARDIZED TO A Z SCORE (LEVINE EEA). RESULTS: AMONG 2846 PARTICIPANTS (MEDIAN AGE, 30.3 [IQR, 9.3-41.5] YEARS; 53% MALES), THE CROSS-SECTIONAL ANNUAL CHANGE IN EA_LEVINE WAS HIGHER IN CHILDREN (1.63 YEARS) AND ADOLESCENTS (1.14 YEARS), AND THE ADJUSTED LEAST-SQUARES MEAN OF LEVINE EEA WAS LOWER IN CHILDREN (-0.22 YEARS) AND OLDER ADULTS (-1.70 YEARS). EACH 1-SD INCREASE IN LEVINE EEA WAS ASSOCIATED WITH INCREASED RISK OF DEVELOPING EARLY-ONSET OBESITY (ODDS RATIO [OR], 1.46; 95% CI, 1.19-1.78), HIGH SEVERITY/BURDEN OF CHCS (OR, 1.13; 95% CI, 1.03-1.24), AND LATE MORTALITY (HAZARD RATIO, 1.75; 95% CI, 1.35-2.26). CONCLUSIONS AND RELEVANCE: THE FINDINGS OF THIS STUDY SUGGEST THAT EAA MEASURED IN CHILDREN AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER IS ASSOCIATED WITH EARLY-ONSET OBESITY, SEVERITY/BURDEN OF ALL CHCS, AND LATE MORTALITY. EVALUATING EAA MAY HELP IDENTIFY SURVIVORS OF CHILDHOOD CANCER AT INCREASED RISK FOR EARLY-ONSET OBESITY, MORBIDITY IN GENERAL, AND MORTALITY.	2023	
                                                                                                                                                                                                                                     
18  4246  41 METHYLATION STATUS OF THE T-CADHERIN GENE PROMOTOR IN PERIPHERAL BLOOD MONONUCLEAR CELLS IS ASSOCIATED WITH HBV-RELATED HEPATOCELLULAR CARCINOMA PROGRESSION. DNA METHYLATION IS ONE OF THE EPIGENETIC MECHANISMS TO REGULATE GENE EXPRESSION AND FREQUENTLY OCCURS IN HUMAN CANCER CELLS. T-CADHERIN (CDH13) IS A NEW MEMBER OF THE CADHERIN SUPERFAMILY AND POSSESSES MULTIPLE FUNCTIONS. OUR STUDY INCLUDED 26 NORMAL CONTROLS (NCS), 65 CHRONIC HEPATITIS B PATIENTS (CHB), 14 LIVER CIRRHOSIS PATIENTS (LC) AND 157 HEPATOCELLULAR CARCINOMA PATIENTS (HCC). WE MAINLY FOCUSED ON THE MRNA EXPRESSION AND METHYLATION STATUS OF CDH13 IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS), WHICH WERE DETECTED BY SEMI-QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (RT-QPCR) AND METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) RESPECTIVELY. THE CDH13 MRNA LEVEL WAS LOWER IN HCC, ESPECIALLY IN EARLY-STAGE OF HCC THAN IN NCS AND CHB GROUPS (P < 0.05). METHYLATION FREQUENCY OF THE CDH13 PROMOTER WAS SIGNIFICANTLY HIGHER IN HCC PATIENTS THAN IN THE NCS AND CHB GROUPS (67.52 % VS 0.00 %, P < 0.001, 67.52 % VS 52.31 %, P < 0.05, RESPECTIVELY). CDH13 MRNA LEVEL WAS SIGNIFICANTLY AND RELATIVELY LOWER IN METHYLATED GROUPS THAN IN UNMETHYLATED GROUPS AMONG THE WHOLE PARTICIPANTS. THE METHYLATION LEVEL OF CDH13 PROMOTER IN HCC MIGHT BE INFLUENCED OR PARTLY INFLUENCED BY SOME CRITICAL FACTORS SUCH AS TBIL, ALB AND AFP (P < 0.05). AS AN IMPORTANT FACTOR IN SIGNALING PATHWAY REGULATING BY CDH13 TO PROMOTE CARCINOGENESIS, JNK LEVEL WAS SIGNIFICANTLY HIGHER IN HCC WHICH HAD A HIGHER METHYLATION FREQUENCY THAN IN NCS, CHB AND LC (P < 0.05). FURTHERMORE, THE COMBINATION OF THE METHYLATED CDH13 LEVEL AND AFP LEVEL SHOWED A BETTER SCORE: AUC = 0.796 (SE = 0.031, 95 %CI 0.735-0.857; P < 0.001) IN MALE AND AUC = 0.832 (SE = 0.057, 95 %CI 0.721-0.944; P < 0.001) IN FEMALE COMPARED TO AFP ALONE FOR DIAGNOSING HCC FROM NCS, CHB AND LC. THE METHYLATION OF CDH13 PROMOTER WAS AN INDEPENDENT PREDICTOR FOR ASSESSING THE PROGNOSIS OF HCC PATIENTS (R=-1.378 P < 0.05). IN CONCLUSION, HYPERMETHYLATION OF CDH13 IN PBMCS WAS ASSOCIATED WITH THE UNDEREXPRESSION OF MRNA AND THE HIGH RISK OF HCC. THE METHYLATION STATUS OF THE CDH13 PROMOTER IN PBMCS WAS A POTENTIAL NONINVASIVE BIOMARKER TO PREDICT THE PROGNOSIS OF HCC PATIENTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19  1953  35 EPIGENETIC AGE ACCELERATION AND CHRONIC HEALTH CONDITIONS AMONG ADULT SURVIVORS OF CHILDHOOD CANCER. BACKGROUND: MOUNTING EVIDENCE SUPPORTS THE OCCURRENCE OF ACCELERATING AGING AMONG LONG-TERM SURVIVORS OF CHILDHOOD CANCER. WE AIMED TO INVESTIGATE EPIGENETIC AGE ACCELERATION (EAA) IN SURVIVORS AND EVALUATE ASSOCIATIONS BETWEEN EAA, TREATMENT EXPOSURES, HEALTH BEHAVIORS, AND CHRONIC HEALTH CONDITIONS (CHCS). METHODS: GENOME-WIDE METHYLATION DATA WERE GENERATED WITH INFINIUM EPIC BEADCHIP ON BLOOD-DERIVED DNA FROM 2139 SURVIVORS AND 282 FREQUENCY MATCHED CONTROLS FROM THE ST JUDE LIFETIME COHORT STUDY. EAAS WERE ESTIMATED AS RESIDUALS FROM A LINEAR REGRESSION OF EPIGENETIC AGE (LEVINE'S CLOCK) AGAINST CHRONOLOGICAL AGE. ADJUSTED LEAST SQUARE MEAN (ALSM) OF EAA WAS CALCULATED AND COMPARED BETWEEN SURVIVORS AND CONTROLS, ACROSS TREATMENT EXPOSURES AND HEALTH BEHAVIORS. ASSOCIATIONS OF EAA WITH 20 CLINICALLY ASSESSED CHCS WERE EVALUATED WITH MULTIVARIABLE PIECEWISE-EXPONENTIAL MODELS. ALL STATISTICAL TESTS FOR P VALUES BELOW WERE 2-SIDED. RESULTS: EAA WAS STATISTICALLY SIGNIFICANTLY HIGHER IN SURVIVORS THAN CONTROLS (ALSM = 0.63, 95% CONFIDENCE INTERVAL [CI] = 0.26 TO 1.01 VS -3.61, 95% CI = -4.43 TO 2.80). IN A MULTIVARIABLE MODEL AMONG SURVIVORS, STATISTICALLY SIGNIFICANTLY HIGHER EAA (P < .05) WAS OBSERVED IN THOSE EXPOSED TO CHEST RADIOTHERAPY, ABDOMEN OR PELVIC RADIOTHERAPY, ALKYLATING AGENTS, GLUCOCORTICOIDS, OR EPIPODOPHYLLOTOXINS. COMPARED WITH SURVIVORS WITH FAVORABLE HEALTH BEHAVIORS (ALSM = 0.26, 95% CI=-0.36 TO 0.87), EAA WAS STATISTICALLY SIGNIFICANTLY HIGHER AMONG SURVIVORS WITH INTERMEDIATE (ALSM = 1.07, 95% CI = 0.59 TO 1.54) OR UNFAVORABLE HEALTH BEHAVIORS (ALSM = 1.45, 95% CI = 0.60 TO 2.30). IN TIME-TO-EVENT ANALYSES, STATISTICALLY SIGNIFICANT ASSOCIATIONS WERE IDENTIFIED BETWEEN EAA TERTILES AND INCIDENCE OF 7 CHCS: HYPERTENSION (3RD VS 1ST TERTILE, RELATIVE RATE [RR] = 1.83, 95% CI = 1.17 TO 2.83), MYOCARDIAL INFARCTION (RR = 2.91, 95% CI = 1.27 TO 7.21), OBESITY (RR = 1.39, 95% CI = 1.17 TO 1.66), OBSTRUCTIVE PULMONARY DEFICIT (RR = 1.86, 95% CI = 0.95 TO 3.77), PERIPHERAL MOTOR NEUROPATHY (RR = 2.89, 95% CI = 1.24 TO 6.97), PERIPHERAL SENSORY NEUROPATHY (RR = 2.04, 95% CI = 0.99 TO 4.26), AND PULMONARY DIFFUSION DEFICITS (RR = 2.75, 95% CI = 0.95 TO 7.63). CONCLUSIONS: EAA IS STATISTICALLY SIGNIFICANTLY HIGHER IN SURVIVORS OF CHILDHOOD CANCER THAN IN NONCANCER CONTROLS AND IS ASSOCIATED WITH SPECIFIC TREATMENT EXPOSURES, UNFAVORABLE HEALTH BEHAVIORS, AND PRESENCE OF SPECIFIC CHCS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  4244  35 METHYLATION STATUS OF COX-2 IN BLOOD LEUKOCYTE DNA AND RISK OF GASTRIC CANCER IN A HIGH-RISK CHINESE POPULATION. BACKGROUND: METHYLATION IS A COMMON EPIGENETIC MODIFICATION WHICH MAY PLAY A CRUCIAL ROLE IN CANCER DEVELOPMENT. TO INVESTIGATE THE ASSOCIATION BETWEEN METHYLATION OF COX-2 IN BLOOD LEUKOCYTE DNA AND RISK OF GASTRIC CANCER (GC), A NESTED CASE-CONTROL STUDY WAS CONDUCTED IN LINQU COUNTY, SHANDONG PROVINCE, A HIGH RISK AREA OF GC IN CHINA. METHODS: ASSOCIATION BETWEEN BLOOD LEUKOCYTE DNA METHYLATION OF COX-2 AND RISK OF GC WAS INVESTIGATED IN 133 GCS AND 285 SUPERFICIAL GASTRITIS (SG)/ CHRONIC ATROPHIC GASTRITIS (CAG). THE TEMPORAL TREND OF COX-2 METHYLATION LEVEL DURING GC DEVELOPMENT WAS FURTHER EXPLORED IN 74 PRE-GC AND 95 POST-GC SAMPLES (INCLUDING 31 CASES WITH BOTH PRE- AND POST-GC SAMPLES). IN ADDITION, THE ASSOCIATION OF DNA METHYLATION AND RISK OF PROGRESSION TO GC WAS EVALUATED IN 74 PRE-GC SAMPLES AND THEIR RELEVANT INTESTINAL METAPLASIA (IM)/DYSPLASIA (DYS) CONTROLS. METHYLATION LEVEL WAS DETERMINED BY QUANTITATIVE METHYLATION-SPECIFIC PCR (QMSP). ODDS RATIOS (ORS) AND 95% CONFIDENCE INTERVALS (CIS) WERE CALCULATED BY UNCONDITIONAL LOGISTIC REGRESSION ANALYSIS. RESULTS: THE MEDIANS OF COX-2 METHYLATION LEVELS WERE 2.3% AND 2.2% IN GC CASES AND CONTROLS, RESPECTIVELY. NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN COX-2 METHYLATION AND RISK OF GC (OR, 1.15; 95% CI: 0.70-1.88). HOWEVER, THE TEMPORAL TREND ANALYSIS SHOWED THAT COX-2 METHYLATION LEVELS WERE ELEVATED AT 1-4 YEARS AHEAD OF CLINICAL GC DIAGNOSIS COMPARED WITH THE YEAR OF GC DIAGNOSIS (3.0% VS. 2.2%, P=0.01). FURTHER VALIDATION IN 31 GCS WITH BOTH PRE- AND POST-GC SAMPLES INDICATED THAT COX-2 METHYLATION LEVELS WERE SIGNIFICANTLY DECREASED AT THE YEAR OF GC DIAGNOSIS COMPARED WITH PRE-GC SAMPLES (1.5% VS. 2.5%, P=0.02). NO SIGNIFICANT ASSOCIATION BETWEEN COX-2 METHYLATION AND RISK OF PROGRESSION TO GC WAS FOUND IN SUBJECTS WITH IM (OR, 0.50; 95% CI: 0.18-1.42) OR DYS (OR, 0.70; 95% CI: 0.23-2.18). ADDITIONALLY, WE FOUND THAT ELDER PEOPLE HAD INCREASED RISK OF COX-2 HYPERMETHYLATION (OR, 1.55; 95% CI: 1.02-2.36) AND SUBJECTS WHO EVER INFECTED WITH H. PYLORI HAD DECREASED RISK OF COX-2 HYPERMETHYLATION (OR, 0.54; 95% CI: 0.34-0.88). CONCLUSIONS: COX-2 METHYLATION EXISTS IN BLOOD LEUKOCYTE DNA BUT AT A LOW LEVEL. COX-2 METHYLATION LEVELS IN BLOOD LEUKOCYTE DNA MAY CHANGE DURING GC DEVELOPMENT.	2015